The cystatin superfamily is an evolutionarily related group of proteins consisting of at least three families, i.e., stefins (type 1), cystatins (type 2), and kininogens (type 3). See, for example, Barrett, TIBS 12: 193-196, 1987. Generally, stefin family members are unglycosylated proteins consisting of about 100 amino acids that are devoid of disulfide bonds. In contrast, cystatin family members are proteins consisting of about 115 amino acids and characterized by two disulfide bonds in the carboxy-terminal region of the protein. Finally, kininogens contain three regions containing two disulfide loops, similar to the carboxy terminal domain found in members of the cystatin family. The cystatin superfamily are inhibitors of cysteine proteinases (also referred to as cysteine proteases) and are believed to function in a protective role with regard to pathological action of endogenous or exogenous cysteine proteinases. It is believe that cystatins form equimolar reversible complexes with cysteine proteinases.
Cystatin-like proteins have also been identified. One such protein, cystatin-related epididymal specific gene (CRES) does not contain the conserved sequence motifs necessary for cysteine proteinase inhibitory activity (Cornwell et al., Mol. Endocrinol. 6:1653-64, 1992 and Cornwell and Hann, Mol. Reprod. Dev. 41:37-46, 1995). Also, unlike the ubiquitous expression of many of the cystatins, CRES is restricted to the proximal caput epididymal epithelium and testis. CRES expression is stage specific during spermatogenesis and CRES is found in both round and elongating spermatids suggesting a specialized role during spermatogenesis. Cystatins are also found with male reproductive tissues and secretions. Cystatin C for example is found in highest abundance in human semen and participates in spermatogenesis and spermiogenesis and is associated with the sperm throughout its time in the male genital tract (Esnard wt al., FEBS Lett. 300:131-5, 1992). Testatin is believed to be involved in early testis development. Expression is restricted to fetal gonads and adult testis and it is expressed during testis cord formation in pre-Sertoli cells (Tohonen et al., Proc. Natl. Acad. Sci. USA 95:14208-13, 1998).
Proteins capable of modulating spermatogenesis are sought for the study, diagnosis and treatment of conditions associated with reproductive disorders. The present invention provides such polypeptides for these and other uses that should be apparent to those skilled in the art from the teachings herein.